Schizophrenia (SCZ) and Manic-Depressive Illness (MDI) are devastating psychiatric syndromes, affecting at least 1% of the American population. Family, twin and adoption studies conducted over the past half century consistently implicate heredity in the pathogenesis of these illnesses. Linkage analyses with DNA markers - coupled with novel candidate gene studies - holds great promise to elucidate the genetics of neurobiology of some forms of SCZ and MDI. Previous grant support, from both private and ADAMHA sources, has allowed Dr. Byerley to ascertain 12 multiplex schizophrenia pedigrees as well as 12 high density bipolar families. During the course of this work, Dr. Byerley conducted over 500 SADS-L interviews and over 150 follow-up SADS-L interviews. In addition, Dr. Byerley coordinated candidate gene studies (e.g., the D1, D2, D3, D4, and D5 dopamine receptors) as well as genome scanning techniques in a subset of pedigrees. The primary aim of Dr. Byerley's work is to test the hypothesis that major loci underlie SCZ and MDI in a subgroup of families. this will be carried out by (1) ascertaining at least eight additional SCZ pedigrees as well as eight MDI families and (2) genotyping studies with highly polymorphic simple sequence repeat markers, polymorphic brain cDNAs, and selected candidate genes.